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Article Open Access

Macrolides sensitize EGFR-TKI-induced non-apoptotic cell death via blocking autophagy flux in pancreatic cancer cell lines

  • Authors:
    • Shuntaro Mukai
    • Shota Moriya
    • Masaki Hiramoto
    • Hiromi Kazama
    • Hiroko Kokuba
    • Xiao-Fang Che
    • Tomohisa Yokoyama
    • Satoshi Sakamoto
    • Akihiro Sugawara
    • Toshiaki Sunazuka
    • Satoshi Ōmura
    • Hiroshi Handa
    • Takao Itoi
    • Keisuke Miyazawa
  • View Affiliations / Copyright

    Affiliations: Department of Gastroenterology and Hepatology, Tokyo Medical University, Tokyo, Japan, Department of Biochemistry, Tokyo Medical University, Tokyo, Japan, Laboratory of Electron Microscopy, Tokyo Medical University, Tokyo, Japan, Department of Clinical Oncology, Tokyo Medical University, Tokyo, Japan, Department of Biological Information, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan, Kitasato Institute for Life Sciences and Graduate School of Infection Control Sciences, Kitasato University, Tokyo, Japan, Department of Nanoparticle Translational Research, Tokyo Medical University, Tokyo, Japan
    Copyright: © Mukai et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 45-54
    |
    Published online on: November 9, 2015
       https://doi.org/10.3892/ijo.2015.3237
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Abstract

Pancreatic cancer is one of the most difficult types of cancer to treat because of its high mortality rate due to chemotherapy resistance. We previously reported that combined treatment with gefitinib (GEF) and clarithromycin (CAM) results in enhanced cytotoxicity of GEF along with endoplasmic reticulum (ER) stress loading in non-small cell lung cancer cell lines. An epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) such as GEF induces autophagy in a pro-survival role, whereas CAM inhibits autophagy flux in various cell lines. Pronounced GEF-induced cytotoxicity therefore appears to depend on the efficacy of autophagy inhibition. In the present study, we compared the effect on autophagy inhibition among such macrolides as CAM, azithromycin (AZM), and EM900, a novel 12-membered non-antibiotic macrolide. We then assessed the enhanced GEF-induced cytotoxic effect on pancreatic cancer cell lines BxPC-3 and PANC-1. Autophagy flux analysis indicated that AZM is the most effective autophagy inhibitor of the three macrolides. CAM exhibits an inhibitory effect but less than AZM and EM900. Notably, the enhancing effect of GEF-induced cytotoxicity by combining macrolides correlated well with their efficient autophagy inhibition. However, this pronounced cytotoxicity was not due to upregulation of apoptosis induction, but was at least partially mediated through necroptosis. Our data suggest the possibility of using macrolides as ‘chemosensitizers’ for EGFR-TKI therapy in pancreatic cancer patients to enhance non-apoptotic tumor cell death induction.
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Copy and paste a formatted citation
Spandidos Publications style
Mukai S, Moriya S, Hiramoto M, Kazama H, Kokuba H, Che X, Yokoyama T, Sakamoto S, Sugawara A, Sunazuka T, Sunazuka T, et al: Macrolides sensitize EGFR-TKI-induced non-apoptotic cell death via blocking autophagy flux in pancreatic cancer cell lines. Int J Oncol 48: 45-54, 2016.
APA
Mukai, S., Moriya, S., Hiramoto, M., Kazama, H., Kokuba, H., Che, X. ... Miyazawa, K. (2016). Macrolides sensitize EGFR-TKI-induced non-apoptotic cell death via blocking autophagy flux in pancreatic cancer cell lines. International Journal of Oncology, 48, 45-54. https://doi.org/10.3892/ijo.2015.3237
MLA
Mukai, S., Moriya, S., Hiramoto, M., Kazama, H., Kokuba, H., Che, X., Yokoyama, T., Sakamoto, S., Sugawara, A., Sunazuka, T., Ōmura, S., Handa, H., Itoi, T., Miyazawa, K."Macrolides sensitize EGFR-TKI-induced non-apoptotic cell death via blocking autophagy flux in pancreatic cancer cell lines". International Journal of Oncology 48.1 (2016): 45-54.
Chicago
Mukai, S., Moriya, S., Hiramoto, M., Kazama, H., Kokuba, H., Che, X., Yokoyama, T., Sakamoto, S., Sugawara, A., Sunazuka, T., Ōmura, S., Handa, H., Itoi, T., Miyazawa, K."Macrolides sensitize EGFR-TKI-induced non-apoptotic cell death via blocking autophagy flux in pancreatic cancer cell lines". International Journal of Oncology 48, no. 1 (2016): 45-54. https://doi.org/10.3892/ijo.2015.3237
Copy and paste a formatted citation
x
Spandidos Publications style
Mukai S, Moriya S, Hiramoto M, Kazama H, Kokuba H, Che X, Yokoyama T, Sakamoto S, Sugawara A, Sunazuka T, Sunazuka T, et al: Macrolides sensitize EGFR-TKI-induced non-apoptotic cell death via blocking autophagy flux in pancreatic cancer cell lines. Int J Oncol 48: 45-54, 2016.
APA
Mukai, S., Moriya, S., Hiramoto, M., Kazama, H., Kokuba, H., Che, X. ... Miyazawa, K. (2016). Macrolides sensitize EGFR-TKI-induced non-apoptotic cell death via blocking autophagy flux in pancreatic cancer cell lines. International Journal of Oncology, 48, 45-54. https://doi.org/10.3892/ijo.2015.3237
MLA
Mukai, S., Moriya, S., Hiramoto, M., Kazama, H., Kokuba, H., Che, X., Yokoyama, T., Sakamoto, S., Sugawara, A., Sunazuka, T., Ōmura, S., Handa, H., Itoi, T., Miyazawa, K."Macrolides sensitize EGFR-TKI-induced non-apoptotic cell death via blocking autophagy flux in pancreatic cancer cell lines". International Journal of Oncology 48.1 (2016): 45-54.
Chicago
Mukai, S., Moriya, S., Hiramoto, M., Kazama, H., Kokuba, H., Che, X., Yokoyama, T., Sakamoto, S., Sugawara, A., Sunazuka, T., Ōmura, S., Handa, H., Itoi, T., Miyazawa, K."Macrolides sensitize EGFR-TKI-induced non-apoptotic cell death via blocking autophagy flux in pancreatic cancer cell lines". International Journal of Oncology 48, no. 1 (2016): 45-54. https://doi.org/10.3892/ijo.2015.3237
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